The Genetics of Pituitary Adenomas

The Genetics of Pituitary Adenomas
-Monica Fedele, Giovanna Maria Pierantoni and Alfredo Fusco (2011). The Genetics of Pituitary Adenomas, Contemporary Aspects of Endocrinology, Dr. Evanthia Diamanti-Kandarakis (Ed.), ISBN: 978-953-307-357-6, InTech, Available from: http://www.intechopen.com/books/contemporary-aspects-of-endocrinology/the-genetics-of-pituitary-adenomas

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations
-Haglund F, et al. PLoS ONE May 2012, Volume 7, Issue 5, e36448.

• "...the prolactin receptor is highly abundant in human parathyroid tissues"
• "...PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours."
• "Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways."
• "These data suggest a role of the prolactin receptor in parathyroid adenomas."

The Cabergoline-Resistant Prolactinoma Patient: New Challenges

The Cabergoline-Resistant Prolactinoma Patient: New Challenges
-Molitch M. The Journal of Clinical Endocrinology & Metabolism December 1, 2008 vol. 93 no. 12 4643-4645, doi: 10.1210/jc.2008-2244

• "11 of 60 previously untreated patients (18.3%) required more than 2 mg/wk cabergoline to normalize PRL levels. Of these, four required 3 mg/wk, two required 6 mg/wk, four required 9 mg/wk, and one required 11 mg/wk to normalize PRL levels."
  
• "Of 150 patients, normalization of PRL was eventually achieved in all but one, but doses had to be raised to high levels in many."

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas
-Casanueva F, et al. Clinical Endocrinology (2006) 65, 265–273

• "Doses [of cabergoline] over 3 mg per week are rarely necessary."

Cabergoline Resistance in Pediatric Prolactinomas

Cabergoline Resistance in Pediatric Prolactinomas
-Spinks J, et al. Journal of Pediatric Hematology/Oncology May 2009 - Volume 31 - Issue 5 - pp 377-379 doi: 10.1097/MPH.0b013e31819b71eb

• "We report 3 cases of cabergoline resistance in adolescents with prolactinomas. All patients failed to respond to conventional doses of cabergoline."

Dopamine agonist-resistant prolactinomas

Dopamine agonist-resistant prolactinomas
-Oh MC, Aghi MK Journal of Neurosurgery 2011 May;114(5):1369-79. published online January 7, 2011; DOI: 10.3171/2010.11.JNS101369.

• "Dopamine agonist-resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions."
  
• "...slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy."
  
• "...a minimum pharmacological definition of dopamine agonist resistance would seem to require a failure to respond to 3 months of treatment with up to 3.5 mg of cabergoline per week."
  
• "Although very rare, secondary or acquired resistance to dopamine agonist therapy has also been described, in which patients who were initially responsive to... either bromocriptine or cabergoline, later develop dopamine agonist resistance, with elevated prolactin levels and sometimes an enlarging tumor volume several years after beginning treatment... According to a recent report... there have been only 5 reported instances of patients who demonstrated secondary resistance to dopamine agonist therapy (2 to bromocriptine and 3 to cabergoline).
  
• DARPs (dopamine agonist resistant prolactinomas) are more likely to exhibit cavernous sinus invasion... [71% vs 10% for dopamine agonist-responsive prolactinomas]."
  
• "DARPs typically do not metastatize."
  
• "Transsphenoidal surgery is recommended for prolactinomas instead of medical treatment if
  • ...2) inadequate prolactin reduction despite high cabergoline doses...
    
  • 3) a female patient desires fertility, which may not occur while on dopamine agonists...
    
  • 5) the patient cannot tolerate dopamine agonist therapy due to side effects.
• transsphenoidal surgery:
  • prolactin was normalized in 36% of patients with DARPs in one study.
    
  • prolactin was normalized in 75% of patients with DARPs that were microprolactinomas.
    
  • "Temozolomide... has been used to treat 3 patients with cabergoline-resistant DARPs... with good results in all 3 cases."

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings
-Kovacs K, et al. Human Pathology Volume 38, Issue 1 , Pages 185-189, January 2007

• "Based on the clinical, laboratory, and morphological findings, we recommend temozolomide therapy in patients with pituitary tumors not responding adequately to other treatment options."

The Endoscopic Endonasal Transsphenoidal Approach to the Suprasellar Cistern

The Endoscopic Endonasal Transsphenoidal Approach to the Suprasellar Cistern
-Schwartz T, et al. Clinical Neurosurgery, Volume 54, 2007.

• Description of endoscopic transsphenoidal surgery.

Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996–2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume

Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996–2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume
-Barker F, II, et al. Journal of Clinical Endocrinology & Metabolism 88(10):4709–4719, ©2003 by The Endocrine Society, doi: 10.1210/jc.2003-030461

• Results of transsphenoidal surgery for pituitary tumors, as a function of hospital volume, surgeon volume, and more.

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas
-Hofstetter C, et al. Neurosurg Focus 30 (4):E10, 2011

• Description of endoscopic endonasal transsphenoidal surgery.
• Results from the resection of 86 functional pituitary adenomas at Weill Cornell Medical College, New York–Presbyterian Hospital, from 2004-2010.

Prolactinomas: Diagnosis and Treatment: Management

Prolactinomas: Diagnosis and Treatment: Management
-Nassiri F, et al. Medscape Education CME Released: 02/29/2012.

• "Despite the effectiveness of [dopamine agonists]... some [patients] do not respond at therapeutic levels or higher. Such patients are considered to be DA resistant. The mechanism of resistance seems to be mediated by a decreased number of D2 receptors without a decreased affinity for DA agonists, and an altered signal transduction mechanism."
• "In resistant patients, treatment options include switching DA agonists, increasing DA agonist dosage beyond convention and surgery and/or radiotherapy."
• "Although doses of 2 mg/week exceed recommended package levels for cabergoline, some patients may require up to 3 mg/day for normalization of PRL levels."
• "Temozolomide therapy has even reduced tumor volume and normalized PRL levels in a resistant macroprolactinoma suggesting a possible role for temozolomide in resistant prolactinomas."

Asymptomatic children with multiple endocrine neoplasia type 1 (MEN1) mutations harbour pancreatic and pituitary tumours

Asymptomatic children with multiple endocrine neoplasia type 1 (MEN1) mutations harbour pancreatic and pituitary tumours
-Newey P, et al. Endocrine Abstracts (2009) 19 P171

• "...These two cases highlight the importance of screening children with MEN1 mutations as early diagnosis and treatment is likely to reduce both morbidity and mortality."

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists
-Babey M, et al. Pituitary Volume 14, Number 3 (2011), 222-230, DOI: 10.1007/s11102-010-0283-y

• "Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery... [Among 34 patients] postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities."
• "Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy."

MEN1 and pituitary adenomas

MEN1 and pituitary adenomas
-Delemer B. Service d’endocrinologie-diabète-nutrition

"MEN1 [pituitary] tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma."

Care for patients with multiple endocrine neoplasia type 1: the current evidence base

Care for patients with multiple endocrine neoplasia type 1: the current evidence base.

-Pieterman CRC, et al. Familial Cancer, Volume 10, Number 1 (2011), 157-171, DOI: 10.1007/s10689-010-9398-6.

• "The endocrine manifestations of MEN1 cannot be viewed upon as coinciding sporadic tumors."
• "In conclusion we state that the care for MEN1 patients is complex and should be provided by a centre of expertise. With the endocrinologist as primary caregiver, all important decisions should be made in a regular meeting of a multidisciplinary team, comprising of an endocrinologist, endocrine surgeon, radiologist, specialist nuclear medicine and paediatrician; if necessary expanded with a neurosurgeon, (radiation) oncologist, pathologist and clinical geneticist."
• Recommended protocol for periodic screening (summarized for patients at least 15 years of age):

  facility	frequency	treatment
  outpatient clinic	Every 2 years	History and physical exam
  labs	Every 2 years	Ionized calcium, chloride, phosphate, parathyroid hormone, fasting glucose, fasting insulin, fasting c-peptide, glucagon, fasting gastrin, pancreatic polypeptide, prolactin, insulin-like growth factor 1, platelet serotonin, chromogranin A
  imaging	Every 2 years	MRI of upper abdomen
  	Every 2-3 years	MRI of pituitary (intravenous contrast with gadolinium
  	Every 3-5 years	CT of thorax

Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study

Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study
-Verges, et al. Journal of Clinical Endocrinology & Metabolism 87(2):457–465, ©2002 by The Endocrine Society.

• Among the 85 prolactinomas [treated surgically, medically, or with radiotherapy] PRL levels were normalized in only 37 patients (44%).
• "Compared with pituitary adenomas in the non-MEN1 population, pituitary lesions in MEN1 are characterized by a higher frequency of macroadenomas and a worse response to treatment. This suggests that pituitary adenomas in MEN1 may be more aggressive than those occurring in the non-MEN1 patients."

The treatment of sporadic versus MEN1-related pituitary adenomas

The treatment of sporadic versus MEN1-related pituitary adenomas
-Beckers A, et al. Journal of Internal Medicine, 2003; 253: 599-605.

• MEN1-related adenomas [appear to be] more aggressive and less responsive to therapy than their sporadic counterparts."
• "...prolactinomas are over-represented in MEN1."
• [In non-invasive, sporadic cases, about] 92% of cases of prolactinoma or hyperprolactinemia were normalized with Cabergoline.
• 10-15% of patients are resistant to Bromocriptine. Cabergoline normalized PRL in more than 70% of patients intolerant or resistant to Bromocriptine.
• "In the future, somatostatin analogues with greater affinity to receptors subtype 5 (SSTR5) -frequently present at the cell surface of prolactinomas- may be tried.
• "Malignancy does not appear a characteristic of pituitary tumours in MEN1."
• "it appears therefore probable that MEN1 pituitary adenomas are more aggressive than the sporadic counterpart."
• In MEN1 patients with pituitary adenomas, "aggressive therapy is more frequently needed!"

Pituitary tumors in patients with MEN1 syndrome

Pituitary tumors in patients with MEN1 syndrome
-Syro LV, et al. Copyright © 2012 Hospital das Clínicas da FMUSP

• "pituitary tumors in MEN1 ...are more often resistant to medical therapy."
• "...normalization of pituitary hypersecretion was much less frequent in MEN1 patients than in non-MEN1 subjects (42% vs. 90%)."

Direct Binding of DNA by Tumor Suppressor Menin

Direct Binding of DNA by Tumor Suppressor Menin
-Ping La, et al. Journal of Biological Chemistry, Vol. 279, No. 47. Nov. 2004.

• "Menin directly binds to double-stranded DNA."
• "The COOH terminus of menin mediates binding to DNA, but MEN1 disease-derived mutations in the COOH terminus abolish the ability of menin to bind DNA."
• "MEN1 disease-related menin mutants also fail to repress cell proliferation as well as cell cycle progression at the G2/M phase."
• "Collectively, these results demonstrate... a novel biochemical activity of menin, binding to DNA, and link its DNA binding to the regulation of cell proliferation."

Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation

Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation
-Dreijerink KM, et al. Nat Clin Pract Endocrinol Metab. 2006 Oct;2(10):562-70.

• "Menin maintains transforming growth factor beta mediated signal transduction involved in parathyroid hormone and prolactin gene expression;"
• "We propose that menin links transcription-factor function to histone-modification pathways and that this is crucial for MEN1 tumorigenesis."

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription
-Huang J, et al. 2012 Nature.

• "...menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but... can have opposite effects on transcription.
• "The menin–JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription."
• "In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket..."

Endocrine Neoplasia

Endocrine Neoplasia
-Sturgeon C, editor. 2010 Springer Science. e-ISBN 978-1-4419-0857-5

• This book includes sections on tumors of the thyroid, parathyroid, adrenal, and pancreas, and a section on multiple endocrine neoplasia. The book's list price is over $150, but I found a 'used' copy in unused condition on Amazon for $5. Can't beat that.

DNA - A Graphic Guide to the Molecule that Shook the World

DNA - A Graphic Guide to the Molecule that Shook the World
-Rosenfield I, et al. 2011 Columbia University Press. ISBN 978-0-231-14270-0

• Don't let the 'comic book' design of this book fool You. This book is a great introduction to DNA and genetics! It's well written -even fun- and it has been extremely helpful in learning the basics of DNA structure, gene transcription, and more. Recommended.

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas
-Henriett Butz, et al. InTech, February 2012, ISBN 978-953-307-879-3.

Knockdown of Menin Affects pre-mRNA Processing

Knockdown of Menin Affects pre-mRNA Processing and Promoter Fidelity at the Interferon-gamma Inducible IRF1 Gene
-Auriemma L, et al. Epigenetics & Chromatin 2012, 5:2 doi:10.1186/1756-8935-5-2.

• MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.
• IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells.

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1
-Wikipedia

• An overview of MEN1.

Multiple endocrine neoplasia type 1: a chromatin writer’s block

Multiple endocrine neoplasia type 1: a chromatin writer’s block -Dreijerink, K. M. A., Lips, C. J. M. and Timmers, H. T. M. (2009). Journal of Internal Medicine, 266: 53–59. doi: 10.1111/j.1365-2796.2009.02115.x

• Menin is important for the writing of histone H3K4 trimethylation.
• In MEN1 tumors, writing of H3K4me3 on specific target genes is blocked.
• Compounds that interfere with the removal of the histone methylation mark are being developed.
• Specific targeting of menin-HMT to treat tumors poses a great challenge for future research.

Genome-Wide Analysis of Menin Binding Provides Insights into MEN1 Tumorigenisis

Genome-Wide Analysis of Menin Binding Provides Insights into MEN1 Tumorigenisis -Scacheri, et al. PLoS Genet. 2006 April; 2(4): e51.

• menin functions as a general regulator of transcription.
• HLXB9 is overexpressed in islets in the absence of menin.

Expression analysis of endogenous menin

Expression analysis of endogenous menin, the product of the multiple endocrine neoplasia type 1 gene, in cell lines and human tissues
-Wauto V, et al.
Int J Cancer. 2000 Mar 15;85(6):877-81.

Menin represses tumorigenesis via repressing cell proliferation

Menin represses tumorigenesis via repressing cell proliferation
-Ting Wu, Xianxin Hua.
Am J Cancer Res. 2011; 1(6): 726–739.

• What does the protein menin do?

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1
-Orphanet J Rare Dis. 2006; 1: 38.

F Marini et al.

• A good introduction to MEN1.

Multiple Endocrine Neoplasia Type 1

Multiple Endocrine Neoplasia Type 1
-National Endocrine and Metabolic Diseases Information Service, National Institutes of Health

• An overview of MEN1.

Endoscopic Removal of Pituitary Tumors

Endoscopic transphenoidal resection of pituitary tumors at UCLA.